1. Field of Invention
This invention relates to novel, substituted pyrrole, pyrazole and triazole compounds, processes for their preparation, pharmaceutical compositions containing them, their use as antihypertensive agents, and as a treatment for congestive heart failure in mammals.
2. Background Including Prior Art
The compounds of this invention inhibit the action of the hormone angiotensin II (AII) and are useful therefore in alleviating angiotensin induced hypertension. The enzyme renin acts on a blood plasma .alpha.-globulin, angiotensinogen, to produce angiotensin I, which is then converted by angiotensin converting-enzyme to AII. The latter substance is a powerful vasopressor agent which has been implicated as a causitive agent for producing high blood pressure in various mammalina species, such as the rat, dog, and man. The compounds of this invention inhibit the action of AII at its receptors on target cells and thus prevent the increase in blood pressure produced by this hormone-receptor interaction. By administering a compound of this invention to a species of mammal with hypertension due to AII, the blood pressure is reduced. The compounds of this invention are also useful for the treatment of congestive heart failure.
M. Gall in U.S. Pat. No. 4,577,020, issued Mar. 18, 1986, discloses anti-psychotic triazoles of the formula: ##STR2## or an enantiomer or stereoisomer thereof, wherein R.sub.4 is
(a) hydrogen PA2 (b) (C.sub.1 -C.sub.3)alkyl, PA2 (c) --CH.sub.2 OH, PA2 (d) --CH.sub.2 OCOCH.sub.3, PA2 (e) --S(O).sub.q CH.sub.3, PA2 (f) --SCH.sub.2 CH.sub.3, or PA2 (g) --R.sub.15 ; PA2 (a) phenyl substituted by zero to 2 chloro, fluoro, bromo, alkyl of from one to 3 carbon atoms, nitro, or alkoxy of from one to 3 carbon atoms, or PA2 (b) phenyl substituted by one trifluoromethyl and zero to one of the previous phenyl substituents; PA2 (a) cis--C(R.sub.3).dbd.CH--CH.sub.2 NR.sub.1 R.sub.2, PA2 (b) trans--C(R.sub.3).dbd.CH--CH.sub.2 NR.sub.1 R.sub.2, PA2 (c) --C(CH.sub.3)(OR.sub.14)--CH.sub.2 --CH.sub.2 NR.sub.1 R.sub.2, PA2 (d) a substituent of the Formula III, or ##STR3## (e) a substituent of the Formula IV; ##STR4## wherein --NR.sub.1 R.sub.2 is (a) --N(CH.sub.3)--CH.sub.2 (CH.sub.2).sub.m --R.sub.25, PA2 (b) --NH--CH.sub.2 (CH.sub.2).sub.m R.sub.25, PA2 (c) a substituent of the Formula V, ##STR5## (d) a substituent of the Formula VI, ##STR6## (e) a substituent of the Formula VII, or ##STR7## (f) --N(CH.sub.3)--(CH.sub.2).sub.3 --CH(R.sub.51).sub.2 ; wherein R.sub.14 is PA2 (a) hydrogen PA2 (b) --COCH.sub.3, or PA2 (c) --COCH.sub.2 CH.sub.3 ; PA2 (a) phenyl, PA2 (b) p-fluorophenyl, or PA2 (c) p-chlorophenyl; PA2 (a) hydrogen or PA2 (b) methyl; PA2 or a pharmacologically acceptable acid addition salt; PA2 or solvate or hydrate thereof. PA2 1) when R.sup.2 .noteq.H, then only one of X, Y or Z can be CR.sup.2 ; PA2 2) when Z=N then Y and X.noteq.CR.sup.2 ; or PA2 3) when Y=N then Z and X.noteq.CR.sup.2 ; and PA2 4) when X=Y=N, then Z.noteq.N; PA2 5) when X=N, Y=Z=CR.sup.2, then with respect to Y, R.sup.2 .noteq.C.sub.3-4 alkyl or C.sub.4 alkenyl and with respect to Z, R.sup.2 .noteq.H or Cl and R.sup.1 .noteq.(CH.sub.2).sub.n OR.sup.4 where n=1 and R.sup.4 =C.sub.1 alkyl, A.noteq.carbon carbon single bond, R.sup.3 .noteq.CO.sub.2 H and R.sup.5 .noteq.H.
wherein R.sub.5, R.sub.15, and R.sub.25 are the same or different and are PA1 wherein W.sub.1 is PA1 wherein R.sub.51 is PA1 wherein R.sub.3 is PA1 wherein the dotted line represents a single or double bond; PA1 wherein m is an integer of from one to 2, inclusive; PA1 wherein n is an integer of from zero to 3, inclusive; and PA1 wherein PA1 q is an integer of from zero to 2, inclusive; PA1 X is ##STR10## hydrogen, pyridyl, or 5-pyrimidyl, or R and X, when taken together, are .dbd.CH.sub.2, or when taken together with the carbon atom to which they are attached form a cycloalkyl ring of 5-8 carbon atoms; and Q is hydrogen or methyl; PA1 R.sub.1 is hydrogen, fluoro, chloro, bromo, methoxy, ethoxy, phenyl, methylthio, methyl, ethyl, nitro, trifluoromethyl, or ##STR11## R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7 and R.sub.8 are independently hydrogen, chloro, or fluoro; PA1 or R.sub.1 and R.sub.2, when taken together with the benzene ring to which they are attached, form a naphthalene ring; PA1 R.sub.3 is hydrogen, fluoro, chloro, trifluoromethyl, methoxy, or nitro; PA1 n is 1 or 2, and PA1 E and G are independently N or CH, provided that E and G may not be N at the same time. PA1 X, Y and Z are independently N or CR.sup.2 with the proviso that PA1 A is a carbon carbon single bond, CO, O, NHCO, OCH.sub.2 ; PA1 R.sup.1 is alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms or (CH.sub.2).sub.n OR.sup.4 provided that when R.sup.1 is (CH.sub.2).sub.n OR.sup.4 then R.sup.2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; PA1 R.sup.2 is H, alkyl of 2 to 6 carbon atoms, alkenyl or alkynyl of 3 to 6 carbon atoms; ##STR15## R.sup.3 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3 ; or ##STR16## R.sup.4 is H or alkyl of 1-4 carbon atoms; R.sup.5 is H, halogen, NO.sub.2, methoxy, or alkyl of 1 to 4 carbon atoms; PA1 R.sup.6 is H, alkyl of 1 to 6 carbon atoms; cycloalkyl of 3 to 6 carbon atoms, (CH.sub.2).sub.m C.sub.6 H.sub.5, OR.sup.7 or NR.sup.8 R.sup.9 ; PA1 R.sup.7 is H, alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, phenyl or benzyl; PA1 R.sup.8 and R.sup.9 independently are H, alkyl of 1 to 4 carbon atoms, phenyl, benzyl or NR.sup.8 R.sup.9 taken together form a ring of the formula ##STR17## Q is NR.sup.10, O or CH.sub.2 ; R.sup.10 is H, alkyl of 1 to 4 carbon atoms or phenyl; PA1 R.sup.11 is alkyl of 1 to 6 carbon atoms or perfluoroalkyl of 1 to 6 carbon atoms, (CH.sub.2).sub.p C.sub.6 H.sub.5 ; PA1 R.sup.12 is H, alkyl of 1 to 4 carbon atoms; or acyl of 1 to 4 carbon atoms; PA1 m is 0 to 6; PA1 n is 1 to 6; PA1 p is 0 to 3; PA1 r is 0 to 1; PA1 t is 0 to 2. PA1 A is a carbon-carbon single bond, or NHCO; PA1 R.sup.1 is alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms; PA1 R.sup.2 is H, alkyl, alkenyl or alkynyl each of 3 to 5 carbon atoms; ##STR18## or (CH.sub.2).sub.n F; R.sup.3 is --CO.sub.2 H, --NHSO.sub.2 CF.sub.3 and ##STR19## R.sup.4 is H or CH.sub.3 R.sup.5 is H; PA1 R.sup.6 is H, alkyl of 1 to 6 carbon atoms, OR.sup.7, or NR.sup.8 R.sup.9 ; PA1 R.sup.7 is alkyl of 1 to 6 carbon atoms; PA1 R.sup.8 and R.sup.9 independently are H, alkyl of 1 to 4 carbon atoms, or taken together with the nitrogen form the ring ##STR20## R.sup.11 is CF.sub.3, alkyl of 1 to 4 carbon atoms or phenyl; m is 0 to 3; PA1 n is 1 to 3; PA1 A is a carbon-carbon single bond PA1 R.sup.1 is alkyl or alkenyl of 3 to 5 carbon atoms or CH.sub.2 OR.sup.4 ; provided that when R.sup.1 is CH.sub.2 OR.sup.4 then R.sup.2 is alkyl or alkenyl of 3 to 5 carbon atoms; PA1 R.sup.2 is alkyl or alkenyl of 3 to 5 carbon atoms, CH.sub.2 OR.sup.4, COR.sup.6, ##STR21## R.sup.6 is H, OH, alkyl of 1 to 4 carbon atoms; R.sup.7 is alkyl of 1 to 4 carbon atoms;
Hirsch, et al., in European Patent Application 165,777, filed June 14, 1985, disclose N-substituted imidazole and triazole compounds in preparation of medicaments for inhibiting aromatase or preventing or treating estrogen dependent diseases. These compounds are described by the following formula: ##STR8## wherein R is ##STR9## hydrogen, C.sub.3 -C.sub.8 cycloalkyl, C.sub.1 -C.sub.4 alkyl, or acetenyl;
where
Japanese Patent Application J4 9101-372 discloses anti-inflammatory pyrazoles of the formula ##STR12## where R is tolyl, p-nitrophenyl, benzyl and phenethyl.
Japanese Patent Application J4 9042-668 discloses the preparation of 1-p-chlorobenzyl-3-methyl-2-pyrazolin-5-one. ##STR13##
Pals et al., Circulation Research, 29, 673 (1971) describe that the introduction of a sarcosine residue in position 1 and alanine in position 8 of the endogenous vasoconstrictor hormone AII to yield an (octa)peptide that blocks the effects of AII on the blood pressure of pithed rats. This analog, [Sar.sup.1, Ala.sup.8 ] AII, initially called "P-113" and subsequently "Saralasin", was found to be one of the most potent competitive antagonists of the actions of AII, although, like most of the so-called peptide-AII-antagonists, it also possessed agonistic actions of its own. Saralasin has been demonstrated to lower arterial pressure in mammals and man when the (elevated) pressure is dependent on circulating AII (Pals et al., Circulation Research, 29, 673 (1971); Streeten and Anderson, Handbook of Hypertension, Vol. 5, Clinical Pharmacology of Antihypertensive Drugs, A. E. Doyle (Editor), Elsevier Science Publishers B.V., p. 246 (1984). However, due to its agonistic character, saralasin generally elicits pressor effects when the pressure is not sustained by AII. Being a peptide, the pharmacological effects to saralasin are relatively short-lasting and are only manifest after parenteral administration, oral doses being ineffective. Although the therapeutic uses of peptide AII-blockers, like saralasin, are severely limited due to their oral ineffectiveness and short duration of action, their major utility is as a pharmaceutical standard.
To date there are no known non-peptide antagonists of AII which are useful orally or which bind in vitro in the IC.sub.50 ranges we observe, other than those disclosed in the co-pending U.S. applications identified above.